Study Results

Comparative Bioavailability Studies

Seven clinical studies comparing the safety and tolerance of SMOFlipid 20% with soybean oil based lipid emulsions have been conducted in a total of 22 healthy volunteers and 459 adult patients. Safety and tolerance were assessed by adverse event profile, laboratory safety parameters and vital signs. Of these seven clinical studies efficacy was compared in addition to safety in five studies.

In two randomised, two- period crossover studies in healthy volunteers, the elimination of triglycerides appeared to be faster for SMOFlipid 20% compared to a standard soybean oil emulsion

Out of 5 randomised, double blind studies, one study was conducted in 249 patients post surgery. Over 5 days of efficacy evaluation revealed that both treatment groups were equivalent with respect to triglyceride concentration in serum. Due to different composition of the two lipid emulsions, SMOFlipid 20% was associated with higher mean concentrations of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and lower mean concentrations of the ω-6 fatty acid linoleic acid compared to a soybean oil emulsion in plasma free fatty acids and in plasma, leukocyte and platelet phospholipids. The ω-3/ω-6 ratio increased significantly in the SMOFlipid 20% group compared to the soybean oil emulsion group

The efficacy was also investigated in the long-term study in 73 patients. Regarding the ratio of ω-6/ω-3 fatty acids in red blood cells (RBC) phospholipids and plasma lipoproteins, differences in favour of SMOFlipid were observed which reflected the composition of SMOFlipid 20% compared to Intralipid 20%

In the five clinical studies performed in adult patients plus the two studies in healthy volunteers, safety and tolerability was considered comparable in the SMOFlipid 20% and comparator groups

Detailed Pharmacology

Pharmacokinetics

Two phase I pharmacokinetics studies have been performed in healthy adult men to examine the intravascular metabolism of SMOFlipid 20% (study FE-SM-01-BE) and the elimination of triglycerides and the pharmacokinetics of other lipid parameters after administration of SMOFlipid 20% (study FE-SM-02-DE). The comparator in both studies was a soybean oil emulsion.

Both studies indicated that SMOFlipid 20% was well metabolized intravascularly and showed advantages over a soybean oil emulsion. Specifically, the less marked increase in triglycerides during infusion of SMOFlipid 20% and the faster elimination after stopping the infusion (i.e. shorter half-life) compared to a soybean oil emulsion are of potential benefit, particularly for patients with a limited triglyceride elimination capacity.

The pharmacodynamic properties of SMOFlipid 20% have not been systematically examined in clinical trials because the individual lipid components have been examined in great depth in many years of previous research. The pharmacodynamic effect of SMOFlipid 20% is expected to be a result of the combined effects of the individual components.

Soybean Oil

Soybean oil is the main source of essential fatty acids in SMOFlipid 20%. Both linoleic and α-linolenic acid are long-chain fatty acids (LCFA; >12 carbon atoms) as well as polyunsaturated fatty acids (PUFAs). PUFAs are important constituents of all cell membrane phospholipids and serve as precursors for the synthesis of lipid mediators called eicosanoids (e.g. prostaglandins and leukotrienes)3. An excess of either ω-6 or ω-3 PUFA in parenteral lipid emulsions may be immunosuppressive. The more balanced the ω-6 to ω-3 ratio, the less immunosuppressive effects of the lipid emulsion in a rat heart allotransplantation model were observed2. According to clinical and experimental data, it has been suggested that the most favorable ω-6:ω-3 ratio is in the range of 2:1 to 4:1,2,3,4,5,6,7. The ratio of ω-6:ω-3 fatty acids in SMOFlipid 20% is approximately 2.5:1.

Medium-chain Triglycerides (MCT)

MCT are more rapidly cleared from the blood stream than long-chain triglycerides (LCT), and MCFA are more rapidly oxidized compared to LCFA8,9, thus providing the body with a form of immediately available energy. MCFA are not stored in fat tissue and do not accumulate in the liver10,11,12. Intravenous MCT administration has not been associated with fatty infiltration of the iver or hepatic dysfunction13,14. Hepatic metabolism of MCFA results in stimulation of synthesis of ketone bodies, which can be used as an energy source, but eventually result in acidosis15,16,17,18,19,20. Therefore it is of importance not to include an excessive quantity of MCT in a lipid emulsion. An emulsion containing as much as 75% MCT (and 25% LCT) has been tested in critically ill patients without observing any harmful effects21,22. The amount of MCT (30%) in SMOFlipid 20% is considered safe in that it is lower than in the physical mixtures of MCT/LCT already commercially available in Europe. Replacing a part of LCT by MCT in SMOFlipid 20% reduces the total amount of PUFA, and thus reduces the risk of lipid peroxidation and the associated requirements for antioxidants23.

Monounsaturated fatty acids are less prone to lipid peroxidation than PUFA due to fewer double bonds in the carbon chains.

Fish Oil

Fish oil is characterized by a high content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both of which belong to the ω-3 LCFA family. DHA and EPA are important structural components of cell membranes, and EPA is also a precursor of eicosanoids such as prostaglandins, thromboxanes, and leukotrienes, which for example exhibit a lower inflammatory potential than those derived from ω-6 PUFA arachidonic acid (AA).

Increased intake of ω -3 fatty acids is followed by an increased ω- 3/ω- 6 fatty acid ratio in cell membranes of many cell populations. SMOFlipid contains 15% fish oil. After 5 days post-operative total parenteral nutrition with SMOFlipid ω-3 fatty acids as well as ω-3/ω-6 fatty acid ratio were significantly increased in plasma phospholipids and also in leucocytes and platelets compared to a soybean oil emulsion treatment. As a consequence the EPA/AA ratio was increased resulting in a significantly higher leukotriene B5 (LTB5) release of neutrophils after stimulation vs control group. Leukotriene B4 (derived from AA) remained similar in both groups leading to a significant increased LTB5/LTB4 ratio in the SMOFlipid group only24.

Microbiology

Toxicology

The following toxicological studies have been performed with SMOFlipid

Type of study

Species

SMOFlipidDosesg TG/kg bw/day

Observations and conclusions

Single-Dose Toxicity

Rat

9, 18, 36,

There was no significant toxicity associated with SMOFlipid up to a dose level f 18 g TG/kg bw
(90 ml/kg bw). At 36 g TG/kg bw. toxic signs were observed due to the excessive administration of fluid volume38

Repeat-Dose Toxicity

4-week

Dog

9*

A good tolerance was demonstrated. An adjustment to the intravenous supply of energy was indicated by a dose-related reduction in food intake over time. A dose- and time-related reduction in lymphocytes and thrombocytes was found after high doses, i.e., 9 and 6 g TG/kg bw/day, respectively. Serum cholesterol and phospholipids were increased roughly in proportion to the molar dose of TG and reversed completely within 4 weeks of recovery. Significant morphological changes observed were fatty changes in hepatocytes (fat in the centriacinar region); lungs (foci of granulomatous pneumonia) and kidney (interstitial nephritis). At the end of the 4-week recovery period all afore described drug substance-related changes had subsided39,40.

13-week

Dog

3,6*

Genotoxicity

In vitro

Bacterial gene mutation

S. typhimurium

Up to 40 mg/plate

No mutagenic effects were observed41,42,43.

Chromosomal aberration

Human lymphocytes

Up to 5 mg/ml

HPRT-test

V79 cells

Up to 10 mg/ml

In vivo

Bone marrow cytogenetic test

Rat

10

No mutagenic effect was observed44

Local Tolerance

Rabbit (iv,ia,pv,sc,im)

Dog

SMOFlipid 20% revealed a good local compliance in rabbits after intravenous infusion and following intra-arterial, paravenous and subcutaneous administration. Moderate local changes, which had disappeared after 14 days, were observed after intramuscular administration45.In the 4-week and 13-week repeat dose toxicity intravenous infusion studies in peripheral veins with SMOFlipid 20%, a similar slight to moderate reaction, mainly characterized by induration and swelling, was seen at the infusion sites in dogs from the test, reference and control groups at similar incidence and severity. The vascular changes were consistent with the anticipated response to repeated venipuncture39,40.The osmolality of SMOFlipid 20% is approximately 270 mosmol/kg water and similar that of human serum (281-297 mosmol/kg water).

*Reference Soybean oil emulsion

**Reference: 0.9% NaCl solution

No reproductive toxicity studies have been performed with SMOFlipid. However studies have been performed with the components of SMOFlipid (LCT, MCT, Olive oil and Fish oil) and did not reveal any toxic potential.

Safety pharmacology studies have not been performed with SMOFlipid. However SMOFlipid repeat dose toxicity studies did not reveal any adverse effects on any organ system or function.

In toxicological studies performed with SMOFlipid no other effects than those expected after high doses of lipids were observed, based on single dose and repeat dose toxicity. No signs of genotoxic potential were detected in the respective studies. In a local tolerance study in rabbits a good local compliance was observed after intravenous infusion and following intra-arterial paravenous and subcutaneous administration. Moderate local changes, which disappeared after 14 days, were observed after intramuscular administration.

In a test in guinea pigs (Maximisation test) fish oil showed moderate dermal sensitization. A systemic antigenicity test gave no indication of evidence of anaphylactic potential of fish oil.